Neurodegeneration is a basic biological and medical problem that remains poorly understood. Discoveries of causal genetic mutations have accelerated understanding the molecular mechanisms of these diseases. Mutations in Cu/Zn superoxide dismutase (SOD1) have been linked to a subset of amyotrophic lateral sclerosis (ALS), a devastating motor neuron degenerative disease that leads to progressive paralysis. Understanding how a large number of SOD1 mutations, mostly single amino acid changes, cause the specific motor neuron degeneration may provide important insight into more prevalent sporadic ALS. To this end, Dr. Wang has developed novel SOD1 transgenic C. elegans and mice that exhibit neuronal dysfunction and locomotor defects. Protein misfolding and aggregation, an increasingly common association with major neurodegenerative diseases, are a main feature of both the invertebrate and the mammalian models. The combination of the genetically tractable C. elegans and the mouse models promises a new avenue toward understanding disease mechanism, including the role of protein aggregation. Initially with Dr. Norwich's mentoring and later as an independent investigator, Dr. Wang will carry out specific experiments 1) to systematically characterize the C. elegans model using physiological, biochemical, and genetic tools;2) to employ unbiased C. elegans genetic tools, e.g. RNAi and mutagenic screening, to identify the important molecular players in the disease pathways;and 3) to employ the C. elegans-to-mouse approach to validate the important genes that play central roles in the neuronal phenotypes of both the invertebrate and the mammalian models. Dr. Wang's long-term objective includes better understanding of protein misfolding in the ageing nervous system. The elucidation may contribute to understanding of neurodegenerative diseases in general that are a major public heath challenge in increasingly aging societies.